Estrogen is, in a sense, an organizing principle for the fetus, promoting readiness for birth and neonatal survival. The placenta provides nearly all of the estrogen that circulates in fetal blood, through secretion in the form of sulfate conjugates of estradiol and related estrogens. These sulfate conjugates are formed in the placenta by the enzyme estrogen sulfotransferase (SULT1E1), which is highly expressed in the placenta. The secreted estrogen sulfate conjugates are converted to free estradiol and related estrogens in target tissues through the action of another enzyme, sulfatase. Triclosan, an antibacterial agent to which people are exposed through use of soaps, toothpaste and other personal care products containing Triclosan, is a very potent inhibitor of SULT1E1. Although many agree that inhibiting SULT1E1 is likely to disrupt estrogen biosynthesis or metabolism, to date, no one has examined the in vivo significance of SULT1E1 inhibition in the fetus. This proposal will use the fetal sheep model of in utero fetal development to examine the consequences of inhibiting placental SULT1E1. One specific aim is proposed. We will test the hypothesis that exposure of fetal sheep to Triclosan will, because of its inhibition of SULT1E1, reduce circulating estrogen concentrations and have genomic actions that are consistent with decreased estrogen action in the fetus. Methodology will include studies in vivo in chronically-catheterized fetal sheep, molecular analysis of the responses to Triclosan in the experimental animals, and in vitro biochemical assessment of the effect of Triclosan on plasma and tissue analyte concentrations. This project is the first in vivo study of the consequences of inhibiting SULT1E1 in the pregnant animal, using an animal model whose estrogen biosynthesis is far closer to the human being than rodent species. As such, it will provide a mechanistic basis for understanding disturbances in pregnancy outcome and fetal development after exposure to Triclosan and will provide a foundation for future experiments. PUBLIC HEALTH RELEVANCE: This project examines the possibility that exposure to triclosan, an antibacterial agent added to numerous personal care products, reduces the supply of estrogen to the fetus and has adverse effects that are mediated by reduced estrogen action.